The multifactorial basis for the pathogenesis of inflammatory bowel disease (IBD) is being increasingly recognized, including the contribution of non immune elements to intestinal immunity and inflammation. Although various cellular components are under active investigation, the role of the acellular extracellular matrix (ECM), has been overlooked. The ECM represents a complex and dynamic mixture of macromolecular proteins with a wide range of biological activities, including a close physical and functional interaction with T-cells. This interaction is primarily mediated by integrins, a unique class of adhesion molecules that serves as a mechanical link and bidirectional transfer system for signals from the outside to the inside of a cell, and vice versa. This proposal will evaluate the role of intestinal ECM in modulation of T-cell function in the context of IBD pathogenesis. To investigate this, we have developed novel systems to study the interaction of intestinal fibroblast-derived ECM with T-cells in a mechanistic fashion. Our preliminary data clearly show that intestinal ECM is able to bind and activate T-cells. More importantly, these responses are altered when ECM derives from fibroblast of IBD-involved mucosa, and the adhesiveness for T-cells is markedly enhanced. Based on these observations, we propose to test the following central hypothesis: The enhanced capacity of IBD ECM to bind T-cells modulates mucosal immunity and contributes to chronic inflammation through integrin-mediated pathways. This central hypothesis will be tested through three specific aims: 1) Investigation of the IBD-associated changes in ECM composition responsible for increased T-cell binding; 2) Investigation of ECM-induced, integrin-mediated modulation of T-cells in normal mucosa; 3) Investigation of ECM-induced, integrin-mediated modulation of T-cells in IBD-involved mucosa. The cellular, biochemical and molecular elements and experimental systems necessary to perform the proposed studies are available, have been tested and proved to be workable. We believe this proposal will generate original information needed for a novel and more global approach to the pathogenesis of IBD.